Project description:The enantioselective pyridinylation is important for providing chiral compounds bearing heterocycles of pharmaceutical interests. 4-CN-pyrinde is extensively applied in the radical pyridinylation reaction, however, its' enantioselective application is highly challenging. To achieve this goal, we propose an electrochemical catalytic activation of 4-CN-pyridine with a chiral transition metal complex instead of direct cathodic reduction. The chiral catalyst acts as the electron mediator and the transition metal catalysis in turn. The radical species from 4-CN-pyridine is captured via radical rebound by chiral catalyst, and undergoes enantioselective pyridinylation reaction. Here, we show the first method for catalytic asymmetric allylic 4-pyridinylation reactions using 4-CN-pyridine under electrochemical conditions.
Project description:Palladium-catalyzed organometallic transformations of free amines are often unsuccessful due to side reactions, such as oxidation, that can occur. However, the ability to furnish the free amine products from these reactions is important for improving the utility and sustainability of these processes, especially for accessing their potential as medicinal and agrochemical agents. Notably, the 3,3-diarylallylamine motif is prevalent in a variety of biologically relevant structures, yet there are few catalytic approaches to their synthesis, and none involving the free amine. Herein, we describe a simple protocol for the arylation of cinnamylamines and the diarylation of terminal allylamines to generate a diverse group of 3,3-diarylallylamine products using a PdII precatalyst. Key features of the method are the ability to access relatively mild conditions that facilitate a broad substrate scope as well as direct diarylation of terminal allylamine substrates. In addition, several complex and therapeutically relevant molecules are included to demonstrate the utility of the transformation.
Project description:A total synthesis of (-)-aspidospermidine via an enantioselective Pd-catalyzed allylic substitution strategy is reported. This represents the first application of a Pd-catalyzed allylic substitution with a 3-substituted indole derivative in the synthesis of Aspidosperma alkaloids. In our synthetic route, the allylic substitution reaction was the stereo defining step. The pentacyclic framework was then constructed in a fully diastereoselective sequence. This culminated in the shortest enantioselective synthesis of aspidospermidine reported to date, in seven linear steps.
Project description:Although the palladium-catalyzed Tsuji-Trost allylic substitution reaction has been intensively studied, there is a lack of general methods to employ simple benzylic nucleophiles. Such a method would facilitate access to "?-2-propenyl benzyl" motifs, which are common structural motifs in bioactive compounds and natural products. We report herein the palladium-catalyzed allylation reaction of toluene-derived pronucleophiles activated by tricarbonylchromium. A variety of cyclic and acyclic allylic electrophiles can be employed with in situ generated (?(6)-C(6)H(5)CHLiR)Cr(CO)(3) nucleophiles. Catalyst identification was performed by high throughput experimentation (HTE) and led to the Xantphos/palladium hit, which proved to be a general catalyst for this class of reactions. In addition to ?(6)-toluene complexes, benzyl amine and ether derivatives (?(6)-C(6)H(5)CH(2)Z)Cr(CO)(3) (Z = NR(2), OR) are also viable pronucleophiles, allowing C-C bond-formation ? to heteroatoms with excellent yields. Finally, a tandem allylic substitution/demetalation procedure is described that affords the corresponding metal-free allylic substitution products. This method will be a valuable complement to the existing arsenal of nucleophiles with applications in allylic substitution reactions.
Project description:A formidable challenge at the forefront of organic synthesis is the control of chemoselectivity to enable the selective formation of diverse structural motifs from a readily available substrate class. Presented herein is a detailed study of chemoselectivity with palladium-based phosphane catalysts and readily available 2-B(pin)-substituted allylic acetates, benzoates, and carbonates. Depending on the choice of reagents, catalysts, and reaction conditions, 2-B(pin)-substituted allylic acetates and derivatives can be steered into one of three reaction manifolds: allylic substitution, Suzuki-Miyaura cross-coupling, or elimination to form allenes, all with excellent chemoselectivity. Studies on the chemoselectivity of Pd catalysts in their reactivity with boron-bearing allylic acetate derivatives led to the development of diverse and practical reactions with potential utility in synthetic organic chemistry.
Project description:Nickel-catalyzed intermolecular allylic substitution of simple alkenes (ethylene and alpha olefins) is described. This method is the first catalytic intermolecular process for direct allylation of nonconjugated, nonstrained simple alkenes. Catalyst loadings as low as 2.5 mol % Ni afford the desired product in high yield in both gram-scale and smaller scale coupling reactions.
Project description:This report describes a nickel-catalyzed allylic substitution process of simple alkenes whereby an important structural motif, a 1,4-diene, was prepared. The key to success is the use of an appropriate nickel-phosphine complex and a stoichiometric amount of silyl triflate. Reactions of 1-alkyl-substituted alkenes consistently provided 1,1-disubstituted alkenes with high selectivity. Insight into the reaction mechanism as well as miscellaneous application of the developed catalytic process is also documented.
Project description:The first Ir-catalyzed enantioselective allylation of trisubstituted allylic electrophiles has been developed. Through modification of the leaving group of allylic electrophiles, we found that trisubstituted allylic phosphates are suitable electrophiles for asymmetric allylation. The reaction of allylic phosphates with enol silanes derived from dioxinones gave allylated products in good yields with high enantioselectivities.
Project description:The first general method for the enantioselective construction of all-carbon quaternary centers on cyclopentanones by enantioselective palladium-catalyzed decarboxylative allylic alkylation is described. Employing the electronically modified (S)-(p-CF3)3-t-BuPHOX ligand, α-quaternary cyclopentanones were isolated in yields up to >99% with ee's up to 94%. Additionally, in order to facilitate large-scale application of this method, a low catalyst loading protocol was employed, using as little as 0.15 mol % Pd, furnishing the product without any loss in ee.
Project description:Detailed studies on the origin of the regioselectivity for formation of branched products over linear products have been conducted with complexes containing the achiral triphenylphosphite ligand. The combination of iridium and P(OPh)3 was the first catalytic system shown to give high regioselectivity for the branched product with iridium and among the most selective for forming branched products among any combination of metal and ligand. We have shown the active catalyst to be generated from [Ir(COD)Cl]2 and P(OPh)3 by cyclometalation of the phenyl group on the ligand and have shown such species to be the resting state of the catalyst. A series of allyliridium complexes ligated by the resulting P,C ligand have been generated and shown to be competent intermediates in the catalytic system. We have assessed the potential impact of charge, metal-iridium bond length, and stability of terminal vs internal alkenes generated by attack at the branched and terminal positions of the allyl ligand, respectively. These factors do not distinguish the regioselectivity for attack on allyliridium complexes from that for attack on allylpalladium complexes. Instead, detailed computational studies suggest that a series of weak, attractive, noncovalent interactions, including interactions of H-bond acceptors with a vinyl C-H bond of the alkene ligand, favor formation of the branched product with the iridium catalyst. This conclusion underscores the importance of considering attractive interactions, as well as repulsive steric interactions, when seeking to rationalize selectivities.